The objective of this work is the synthesis and biological evaluation of new compounds as potential folate antagonists, especially in cancer chemotherapy. These compounds will include analogs of pteroic acid, folic acid and methotrexate in which structural modifications are made at several places in the molecules. Analogs will be prepared in which the C9-N10 bridge is replaced by an aziridine or oxirane ring. These compounds, which contain a reactive 3-membered ring system, might function as irreversible inhibitors of enzymes in the folic acid metabolic system by forming a covalent linkage with the complexing enzyme. Side-chain altered analogs will be prepared in which an additional spacer atom is placed between the phenyl ring and the glutamic acid (or other dibasic acid) side chain. This slight modification may not greatly interfere with the active transport of these compounds into cells, but could result in selective inhibition of folate enzymes. Since most of the biologically important folate coenzymes function through their reduced forms, another area of interest is the preparation of stable 8-substituted 7,8-dihydro analogs and their tetrahydro derivatives. All of the compounds synthesized in this work will be tested in vitro as inhibitors of the enzymes dihydrofolate reductase and thymidylate synthetase from various sources, and also as inhibitors of human lymphoblastic leukemic cells. In vivo antitumor evaluation will be conducted in L1210 leukemic mice. In addition, selected compounds will be screened for antibacterial activity.